ABSTRACT

ObjectiveTo evaluate the specific contact lens-related or other factors that may contribute to the outbreak of Fusarium keratitis.

MethodsA case-control study was conducted of Fusarium keratitis in contact lens users in Singapore from March 1, 2005, to May 31, 2006, and included 61 patients with Fusarium keratitis and 188 population-based and 179 hospital-based control subjects. Interviewers asked about contact lens solution use and other risk factors.

ResultsPatients with Fusarium keratitis were more likely to use ReNu contact lens solutions (Bausch & Lomb, Rochester, NY) 58 [95.1%] of 61 cases) than were either population-based (62 [34.3%] of 181) or hospital-based (50 [30.1%] of 166) control subjects. After controlling for age, sex, contact lens hygiene, and other factors, the use of ReNu with MoistureLoc significantly increased the risk of Fusarium keratitis (odds ratio, 99.3; 95% confidence interval, 18.4-535.4; P<.001), and the risk was 5 times higher compared with the risk with use of ReNu MultiPlus, a multipurpose solution (odds ratio, 21.5; 95% confidence interval, 4.0-115.5; P<.001).

ConclusionsThe use of ReNu contact lens solutions significantly increased the risk of contact lens–related Fusarium keratitis in Singapore. Our data support the recall of ReNu MultiPlus from the Singapore market and the need for further investigations into the role of ReNu MultiPlus in the development of Fusarium keratitis in other populations.

More than 30 million adults in the United States use contact lenses to correct refractive error.1,2Fusarium keratitis is a rare fungal infection of the cornea that is potentially blinding even if detected early and treated aggressively.1- 3 We estimate from previously obtained baseline data that there are approximately 4 incident cases of Fusarium keratitis per year and that only 2 of the 4 incident cases are contact lens–related.4 There are about 224 800 contact lens wearers in Singapore; thus, the baseline incidence of Fusarium keratitis in contact lens wearers is approximately 1 per 100 000 contact lens wearers.5 In early 2006, an unexpected increase in the incidence of Fusarium keratitis was noted in contact lens wearers in Asia and the United States.6- 11 Seventy-eight cases of contact lens–related Fusarium keratitis were reported in Singapore between March 1, 2005, and May 31, 2006,6 and 125 cases were reported from 25 states and 1 territory in the United States.12,13

The cause of this outbreak was unclear. A large percentage of affected individuals in both Singapore and the United States had used multipurpose contact lens solutions known as ReNu MultiPlus and ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY), and as a precautionary measure, on May 15, 2006, Bausch & Lomb announced a worldwide recall of ReNu with MoistureLoc.14 Recently, a multistate case-control study of 45 patients and 78 control subjects was conducted in the United States.15 The finding from this study supported the link between use of ReNu with MoistureLoc and Fusarium keratitis (odds ratio [OR], 13.3; 95% confidence interval [CI], 3.1-119.5), but ReNu MultiPlus solution was not associated with an increased risk of Fusarium keratitis. Available evidence suggests that ReNu with MoistureLoc may be the only contact lens solution linked to the outbreak.15 It is important that we continue to conduct further investigations of all of the various brands of contact lens solutions, including ReNu MultiPlus solution, as well as contact lens hygiene patterns, so that other contributing factors to this unusual international outbreak are not overlooked.

In Singapore, the reported evidence linking ReNu with MoistureLoc and ReNu MultiPlus to Fusarium keratitis has been based on an observational case series.6 We report the primary results of a case-control study performed to evaluate other possible coexisting risk factors to determine the nature and source of the epidemic in Singapore.

METHODS

STUDY DESIGN AND POPULATION

We conducted a nationwide retrospective case-control study with 2 groups of control subjects, hospital-based and community-based populations, which allowed the evaluation and replication of results in 2 different populations.

CASES

Cases (n = 61) were patients with Fusarium keratitis and who wore contact lenses at least once a week for refractive error correction who were seen between March 1, 2005, and May 31, 2006, at the 5 major eye hospitals in Singapore (Singapore National Eye Center, Changi General Hospital, Tan Tock Seng Hospital, National University Hospital, and Mount Elizabeth Hospital) and 1 private ophthalmology clinic. Patients who were wearing bandage contact lenses for therapeutic reasons were excluded. Of the 78 eligible cases reported during this period, 5 patients chose not to participate and 12 could not be contacted.

Fusarium keratitis was defined as any infective corneal lesion in which Fusarium species was cultured from the cornea (n = 51). These corneal specimens were sampled from the base or edge of the lesion and in most cases were cultured on a variety of culture media, including blood agar and Sabouraud dextrose agar. Patients who had clinical findings of fungal keratitis were treated with and responded to antifungal medications; those with corneal cultures with no abnormal findings were also included if Fusarium species could be cultured from the contact lens (n = 7) or contact lens case (n = 3).

Further genetic studies were also performed on cultured Fusarium samples. Species identification was confirmed using 28S ribosomal RNA sequencing.16 The isolates from the eye specimens were studied for genetic relatedness to establish if there was a common source of infection; strain typing was performed using amplified fragment length polymorphism (AFLP; Microbial Adaptor/Core Sequence kit; Applied Biosystems, Foster City, Calif).

POPULATION- AND HOSPITAL-BASED CONTROL SUBJECTS

Control subjects were chosen from individuals who wore contact lenses for the correction of refractive error and had been wearing lenses at least once a week for the 3 months before the study began. Population-based control subjects (n = 188) were contact lens wearers who were seen at 6 private optometry practices in Singapore, randomly selected from 502 contact lens practices listed in the nationwide Contact Lens Practitioners Register, and 4 of 15 branches of the largest chain of optometry shops in Singapore. The population-based control subjects were seen between April 1, 2006, and May 31, 2006. Forty of these individuals refused to participate.

Hospital-based control subjects (n = 179) were contact lens wearers seen at the refractive surgery clinics of 2 major eye hospitals (Singapore National Eye Center and Tan Tock Seng Hospital) because of ophthalmic symptoms unrelated to infective keratitis (eg, dry eye). The hospital-based control subjects were seen between March 1, 2005, and May 31, 2006. Three hospital-based control subjects refused to participate in the study.

Written or verbal informed consent was obtained from all patients or the parents of patients younger than 21 years. The study was approved by the institutional review board of Singapore Eye Research Institute and conformed to the tenets of the Declaration of Helsinki.

RISK FACTOR ASSESSMENT

Trained interviewers masked to the study hypothesis used a standardized form and took approximately 15 minutes to interview each case or control subject. The form included demographic data such as age, sex, race/ethnicity, and total monthly family income. Ethnicity refers to an individual's race as declared by that person on his or her national identity card. The population in Singapore is classified by the Singapore Department of Statistics into 4 categories: Chinese, Malay, Indian, and other.17

Details about the type, brand, and duration of contact lens use and contact lens solutions used in the previous 3 months were elicited. To reduce reporting errors, a list of common contact lenses and solutions sold in Singapore were included. In addition, we asked about contact lens practices based on the wearers' usage and habits before February 2006, when public advisories were released to avoid the use of all ReNu contact lens solutions.

The interviewers asked about the use of contact lenses beyond the recommended replacement date, washing of hands before handling contact lenses, whether the patient slept overnight with contact lenses, the patient's contact lens cleaning regimen, and maintenance of the contact lens case. Other predisposing factors ascertained included recent travel overseas, proximity to construction activity, and outdoor activities.

STATISTICAL ANALYSIS

Cases were initially compared separately from population- and hospital-based controls, and, subsequently, both control groups were analyzed together. We used multiple binary logistic regression with case-control status as the dependent variable to determine associations with age, sex, race/ethnicity, monthly income, and other covariates. We further performed analyses to examine for interactions between contact lens solution type and age, sex, race/ethnicity, lens use past the expiration date, and monthly soft disposable lenses. All statistical analyses were conducted using SPSS software (version 13.0; SPSS Inc, Chicago, Ill).

For all control subjects combined, male subjects had significantly higher risks of Fusarium keratitis. Malays were at highest risk of Fusarium keratitis, but the number of Malay cases and controls was small. Adults who did not work were at 1.9-fold increased risk of Fusarium keratitis compared with those who worked, but this relationship was only of borderline significance (P = .05; Table 1).

The multivariate adjusted OR for ReNu with MoistureLoc (99.3; 95% CI, 18.4-535.4) and ReNu MultiPlus (21.5; 95% CI, 4.0-115.5) were stronger (Table 4). The multivariate OR of ReNu solution use vs non-ReNu solution use was 47.7 (95% CI, 10.9-209.8) for all controls after adjusting for similar factors. There were no interactions between ReNu solution and age, sex, race/ethnicity, use of contact lens past the replacement date, or soft monthly disposable lenses. The use of lenses past the replacement date increased the risk of Fusarium keratitis in all controls (OR, 4.8; 95% CI, 1.7-13.8). Wearing monthly, soft, disposable lenses; swimming with contact lenses; and occupation (not working vs working) did not remain significant in multivariate models. Among the cases, bilateral involvement was present in 3 patients, and in 31 patients (50.8%), the left eye was affected. Eight patients received topical corticosteroid eyedrops before the diagnosis of Fusarium keratitis. Most patients were treated with antifungal medications; topical natamycin, amphotericin B deoxycholate, and voriconazole were commonly used, often in combination. Eight eyes with impending perforation or threatened scleral involvement also received systemic therapy such as oral fluconazole, systemic and oral voriconazole, or oral itraconazole followed by systemic voriconazole. Five eyes required a therapeutic or tectonic corneal transplant in the acute stages of the infection..

Thirty-eight patients had isolates available for 28S ribosomal RNA sequencing, and 37 had a 100% match with the sequence from Fusarium solani CBS490.63 in the GenBank database. The remaining isolate matched Fusarium oxysporum. The results of amplified fragment length polymorphism typing for all the F solani isolates did not show the presence of a single identical clone but showed 7 groups at 80% genetic similarity.

COMMENT

In this national case-control study, we demonstrated that the use of either ReNu with MoistureLoc or ReNu MultiPlus solutions significantly increased the risk of Fusarium keratitis, while controlling for age, sex, race/ethnicity, income, and contact lens hygiene factors. Similar results were found when all controls were combined and when controls were analyzed separately. To our knowledge, this is the first large study with 2 groups of controls and comprehensive assessments of contact lens hygiene factors to determine the exact source of Fusarium keratitis infection in an Asian country.

Our findings concur with the recent case-control study by Chang et al15 that ReNu with MoistureLoc solution increased the risk of Fusarium keratitis. The market share of all ReNu contact lens solutions was estimated to be 30% in Singapore, and on February 20, 2006, the Ministry of Health advised all contact lens users to discontinue use of all ReNu contact lens solutions. Investigations of the product have reportedly not revealed any issues relating to product contamination or sterility.14,18,19 The contact lens solution, however, may not perform as desired under in-use conditions, leading to a decrease in the product's disinfecting capability. The solution could also induce a breach in the corneal epithelium and enhance the entry of Fusarium organisms into the cornea. Bausch & Lomb concluded that ReNu with MoistureLoc's formulation could create biofilms that shield the fungus from the sterilizing agent.18

The findings from our study showed that ReNu MultiPlus solution was also linked to Fusarium keratitis, although this association was 5 times weaker compared with ReNu with MoistureLoc. However, a recent case-control study in the United States15 did not demonstrate a link between ReNu MultiPlus and Fusarium keratitis (OR, 0.7; 95% CI, 0.2-2.8). In Singapore, ReNu MultiPlus solution has been available for the last few years, but there were no reports of an increase in Fusarium keratitis before 2005; perhaps some cases were unreported. However, in Japan, where only ReNu MultiPlus solution is available and ReNu with MoistureLoc is not sold, no contact lens–related Fusarium keratitis has been reported; and we are also unaware of any reported cases in Europe, where both ReNu products are sold. Since May 2006, the number of cases has decreased in the United States, after ReNu with MoistureLoc solution was withdrawn from the market.15 This observation suggests that ReNu MultiPlus may not cause Fusarium keratitis. However, there have been other reports of the use of ReNu MultiPlus in patients with Fusarium keratitis.8,9 Further investigations into the role of ReNu MultiPlus in the development of Fusarium keratitis should be conducted in other populations.

The overall contact lens hygiene practices of cases and controls were not optimal and may have an important role in the pathogenesis of infection. A relatively high percentage of subjects used contact lenses past the replacement date (55% of cases, 40% of population-based controls, and 40% of hospital-based controls), and links with Fusarium keratitis remained positive in multivariable analysis. Male subjects were at higher risk of Fusarium keratitis in multivariate analyses in our study. The sex differences may reflect differences in underlying biological and genetic makeup or different lifestyle factors.

There are several advantages of our study. Cases were detected using microbiological laboratory reports of Fusarium growth in eye-related specimens from all hospitals in Singapore. The microbiological typing results for the clinical isolates show multiple groups; hence, a common source of contamination is unlikely. The availability of both population- and hospital-based controls allowed evaluation of the consistency of results in controls selected by 2 different methods. There were comprehensive assessments using multivariate analyses of possible risk factors and confounders such as contact lens hygiene factors.

All case-control studies may be limited by the presence of differential recall bias in which patients with Fusarium keratitis may overrecall ReNu solution use and controls may underrecall ReNu solution use. Publicity surrounding the ReNu solutions at the time of the case-control study might have exacerbated these recall biases. We attempted to reduce the probability of recall bias by asking about the contact lens habits of cases and controls before the public advisory warning about ReNu solutions. It is possible that the exact type of contact lens solution used by our study participants might not be accurately recalled, although the reporting bias would favor excessive reporting of ReNu with MoistureLoc as opposed to ReNu MultiPlus solution. Selection bias may also occur because hospital cases may not represent all cases with contact lens–related Fusarium keratitis and neither population- nor hospital-based controls seen at optometry practices may truly represent all noninfected contact lens wearers in the population. Nonparticipation bias may lead to different exposure-disease (ReNu solution–Fusarium keratitis) associations in participants compared with nonparticipants. Another limitation is that the precise mechanism by which the solution led to the increase in Fusarium keratitis could not be determined because microbiologic evidence did not suggest a point source contamination.

In summary, we found a strong association with the use of ReNu contact lens solutions (ReNu with MoistureLoc and ReNu MultiPlus) and the risk of developing Fusarium keratitis that was independent of other factors in this case-control study in Singapore. Our data support the worldwide recall and removal of ReNu with MoistureLoc solution from the contact lens solution market. We recommend that future studies of the role of ReNu MultiPlus contact lens solution in Fusarium keratitis should be conducted in other populations.

Submitted for Publication: October 9, 2006; final revision received December 28, 2006; accepted January 2, 2007.

Financial Disclosure: Dr Aung has received travel funding and research grants from Alcon Laboratories Inc.

Funding/Support: This study was supported by the Singapore Eye Research Institute.

Acknowledgment: We thank Grace Wang for technical help in molecular tests and Tse Hsien Koh, Roland Jureen, and Li Yang Hsu for interpreting the results; Victor T. C. Koh and Tong-Leng Tan, who interviewed control subjects as part of the Undergraduate Research Opportunities Program, Yong Loo Lin School of Medicine, National University of Singapore; and the staff of the Disease Control Branch, Ministry of Health, and regulators and technical officers of the Health Sciences Authority, Singapore.

Correspondence

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